The present invention relates to an improved botulinum toxin formulation. In particular the present invention relates to an injectable botulinum toxin-hyaluronic acid formulation which can be administered with reduced local and systemic botulinum toxin induced complications.
A pharmaceutical composition (synonymously a formulation or a composition) is a formulation which contains at least one active ingredient (for example a botulinum neurotoxin) as well as, for example, one or more excipients, buffers, carriers, stabilizers, preservatives and/or bulking agents, and is suitable for administration to a human patient to achieve a desired effect or result. The pharmaceutical compositions disclosed herein can have diagnostic, therapeutic, cosmetic and/or research utility.
Hyaluronic Acid
Hyaluronic acid (also called hyaluronan or sodium hyaluronate) is a naturally occurring polysaccharide found in joints, connective tissue and the eye. Hyaluronic acid is a glycosaminoglycan (a mucopolysaccharide) which is a long unbranched polysaccharide composed of repeating dimeric units of glucuronic acid and N acetyl glucosamine. U.S. Pat. Nos. 4,636,524; 4,713,448; 5,099,013, and 5,143,724 disclose particular hyaluronic acids and methods for making them.
Hyaluronic acid has known therapeutic and cosmetic uses. For example, intra-articular use of hyaluronic acid as a viscosupplement to treat osteoarthritis joint pain is known (eg Orthovisc® (Anika), Durolane (Smith & Nephew), Hyalgan® (Sanofi), Hylastan® (Genzyme), Supartz® (Seikagaku/Smith & Nephew)), Synvisc® (Genzyme), and Euflexxa®, (Ferring)). Hyaluronic acid is also used cosmetically as an injectable dermal filler (eg Juvederm™ (Allergan)).
U.S. patent applications which disclose use of therapeutic agent formulated with a hyaluronic acid include application Ser. No. 10/966,764, filed Oct. 14, 2004, application Ser. No. 11/091,977, filed Mar. 28, 2005, application Ser. No. 11/354,415, Feb. 14, 2006, application Ser. No. 11/741,366, filed Apr. 27, 2007, application Ser. No. 11/828,561, filed Jul. 26, 2007, application Ser. No. 11/039,192, filed Jan. 19, 2005, application Ser. No. 11/116,698, filed Apr. 27, 2005, application Ser. No. 11/695,527, filed Apr. 2, 2007, and application Ser. No. 11/742,350, filed Apr. 30, 2007.
Botulinum Toxin
The anaerobic, gram positive bacterium Clostridium botulinum produces a potent polypeptide neurotoxin called botulinum neurotoxin toxin which causes a neuroparalytic illness in humans and animals referred to as botulism. Botulinum toxin type A is the most lethal natural biological agent known to man. About 50 picograms of a commercially available botulinum toxin type A (purified neurotoxin complex)1 is a LD50 in mice (i.e. 1 unit). One unit of BOTOX® contains about 50 picograms (about 56 attomoles) of botulinum toxin type A complex. One unit (U) of botulinum toxin is defined as the LD50 upon intraperitoneal injection into female Swiss Webster mice weighing 18 to 20 grams each. 1 Available from Allergan, Inc., of Irvine, Calif. under the tradename BOTOX® in 100 unit vials)
Seven, generally immunologically distinct botulinum neurotoxins have been characterized, these being respectively botulinum neurotoxin serotypes A, B, C1, D, E, F and G each of which is distinguished by neutralization with type-specific antibodies. The different serotypes of botulinum toxin vary in the animal species that they affect and in the severity and duration of the paralysis they evoke. Botulinum toxin apparently binds with high affinity to cholinergic motor neurons, is translocated into the neuron and blocks the release of acetylcholine.
Botulinum toxins have been used for the treatment of various therapeutic and cosmetic conditions. A botulinum toxin type A (Allergan, Inc., BOTOX®) has been approved by the U.S. Food and Drug Administration for the treatment of blepharospasm, strabismus, cervical dystonia, hyperhydrosis and glabellar lines.
The molecular weight of the neurotoxic component of a botulinum toxin complex is about 150 kD. Botulinum toxin is typically made by the Clostridial botulinum bacterium as a complex comprising the 150 kD botulinum toxin protein molecule and associated non-toxin proteins. Thus, a botulinum toxin type A complex can be produced by Clostridial bacterium as 900 kD, 500 kD and 300 kD complex forms.
A commercially available botulinum toxin containing pharmaceutical composition is sold under the trademark BOTOX® (available from Allergan, Inc., of Irvine, Calif.). BOTOX® consists of a purified botulinum toxin type A complex, albumin and sodium chloride packaged in sterile, vacuum-dried form. Each vial of BOTOX® contains about 100 units (U) of Clostridium botulinum toxin type A purified neurotoxin complex, 0.5 milligrams of human serum albumin and 0.9 milligrams of sodium chloride in a sterile, vacuum-dried form without a preservative. Other commercially available botulinum neurotoxins approved for use in humans include DYSPORT® (Beaufour Ipsen, Porton Down, England) XEOMIN® (Merz Pharmaceuticals GmbH, Frankfurt, Germany) and MYOBLOC® (Solstice Neurosciences, San Francisco, Calif.).
Botulinum Toxin Complications
Local and systemic complications can occur when a botulinum neurotoxin is administered (as by injection) into a muscle or a subcutaneous tissue for a therapeutic or cosmetic purpose. Complications subsequent to injection of a botulinum neurotoxin for a therapeutic or cosmetic purpose can be due to diffusion of the botulinum neurotoxin from the site of injection into adjacent muscle groups. Examples of known local complications upon injection of a botulinum toxin to treat blepharospasm, strabismus and cervical dystonia follow.
Blepharospasm (uncontrolled blinking) is characterized by involuntary, intermittent, forced eyelid closure. Botulinum toxin has been used to treat various types of blepharospasm, including blepharospasm induced by drugs such as L-dopa or neuroleptics, dystonic eyelid and facial tics in patients with Tourette syndrome, and apraxia of eyelid opening. Treatment of essential blepharospasm with a botulinum toxin requires injection of the neurotoxin into the orbicularis muscle. Unfortunately, the botulinum neurotoxin can diffuse out of this muscle into the deeper levator muscle resulting in ptosis and visual field impairment that can persist for several weeks to months. Additionally, brow ptosis can also occur with deeper diffusion of the botulinum neurotoxin out of the orbicularis muscle into the frontalis muscle. Although the medial aspect of the lower lid does not receive an injection, the botulinum toxin can diffuse into this area leading to a medial ectropion and chronic tearing. Patients can also experience double vision if the botulinum neurotoxin diffuses into the deeper rectus muscles. Uncommonly, unintended diffusion of the botulinum toxin into the zygomaticus major muscle occurs which can lead to an asymmetric facial expression.
Strabismus (crossed eyes) can be treated by injecting a botulinum toxin into individual rectus muscles. For example, the medial rectus muscles can be injected with a botulinum toxin under EMG guidance for treating esotropia. Local inadvertent diffusion of the botulinum toxin into the muscle cone can lead to paralysis of other recti leading to double vision and inadequate correction of the esotropia.
Cervical dystonia is the most common form of focal dystonia and is characterized by sustained abnormal postures or contractions of the neck muscles. Deviation of the head can occur in multiple directions; turning of head (torticollis) is the most common subtype of cervical dystonia. Treatment of cervical dystonia with a botulinum toxin can improve the patient's posture and function and to relieve associated pain. Although the intent of botulinum toxin treatment is to inject into selected muscle group, for example the sternocleidomastoid muscle, occasionally under EMG guidance, local diffusion of the botulinum toxin out of the muscle area may occur causing unintentional paralysis of adjacent muscles. Diffusion of the botulinum neurotoxin into the deep neck muscles can cause weakness of the pharyngeal and esophageal muscles and resultant difficulty with swallowing (dysphagia) occasionally is severe enough to require a modified diet and monitoring for aspiration. Dysarthria, difficulty with speech, can also occur. Dysphagia is a commonly reported adverse event following treatment of cervical dystonia patients with a botulinum toxin. In these patients, there are reports of rare cases of dysphagia severe enough to warrant the insertion of a gastric feeding tube. Aspiration pneumonia and death from dysphagia has also occurred after botulinum toxin administration.
Systemic complications upon local intramuscular injection of a botulinum toxin have also been reported. Thus, respiratory distress following an intramuscular botulinum toxin injection can occur from excessive systemic absorption and paralysis of the diaphragm. A number of cases of systemic botulism-like reaction with generalized weakness including bulbar weakness resolved over several weeks has been reported.
Preclinical studies have demonstrated differences in local vs systemic effects of different commercially available botulinum toxin products. Systemic effects may be due to escape of the intramuscularly administered botulinum toxin into the circulation.
What is therefore needed is a botulinum toxin formulation of which the botulinum toxin therein shows a reduced tendency to diffuse from the site of administration upon local (i.e. intramuscular or subcutaneous) injection of the botulinum toxin formulations, thereby reducing complications and side effects upon botulinum toxin administration for a therapeutic or cosmetic purpose.